rs3802805

Positions:

• chr11-44265016-G-A
• chr11-44265016-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021926.4(ALX4):​c.1074C>T​(p.His358=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,612,836 control chromosomes in the GnomAD database, including 101,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8218 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93155 hom.)
• Consequence: ALX4 NM_021926.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.55

Genes affected

ALX4 (HGNC:450): (ALX homeobox 4) This gene encodes a paired-like homeodomain transcription factor expressed in the mesenchyme of developing bones, limbs, hair, teeth, and mammary tissue. Mutations in this gene cause parietal foramina 2 (PFM2); an autosomal dominant disease characterized by deficient ossification of the parietal bones. Mutations in this gene also cause a form of frontonasal dysplasia with alopecia and hypogonadism; suggesting a role for this gene in craniofacial development, mesenchymal-epithelial communication, and hair follicle development. Deletion of a segment of chromosome 11 containing this gene, del(11)(p11p12), causes Potocki-Shaffer syndrome (PSS); a syndrome characterized by craniofacial anomalies, cognitive disability, multiple exostoses, and genital abnormalities in males. In mouse, this gene has been shown to use dual translation initiation sites located 16 codons apart. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-44265016-G-A is Benign according to our data. Variant chr11-44265016-G-A is described in ClinVar as [Benign]. Clinvar id is 304701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44265016-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALX4	NM_021926.4	c.1074C>T	p.His358=	synonymous_variant	4/4	ENST00000652299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALX4	ENST00000652299.1	c.1074C>T	p.His358=	synonymous_variant	4/4		NM_021926.4	P1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46686 AN: 152044 Hom.: 8203 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.336

GnomAD3 exomes AF: 0.373 AC: 93097 AN: 249426 Hom.: 19228 AF XY: 0.369 AC XY: 49992 AN XY: 135324

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.548

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.350 AC: 511825 AN: 1460674 Hom.: 93155 Cov.: 72 AF XY: 0.351 AC XY: 254850 AN XY: 726672

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.558

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.521

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.348

GnomAD4 genome AF: 0.307 AC: 46736 AN: 152162 Hom.: 8218 Cov.: 33 AF XY: 0.313 AC XY: 23267 AN XY: 74360

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.534

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.341

Alfa AF: 0.324 Hom.: 9792

Bravo AF: 0.312

Asia WGS AF: 0.477 AC: 1655 AN: 3478

EpiCase AF: 0.329

EpiControl AF: 0.326

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parietal foramina 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2018	- -

Frontonasal dysplasia with alopecia and genital anomaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.1
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3802805; hg19: chr11-44286566; COSMIC: COSV61327994;